Potential Adverse Effects of Proton Pump Inhibitors in the Elderly
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Potential Adverse Effects of Proton Pump lnhibitors in the Elderly Ami Kapadia, MD, Daisy Wynn, MD, and Brooke Salzman, MD Introduction dence of side effects is similar to placebo, which is less than Since the introduction of omeprazole in 1989, proton 5%.’0 The most common side effects reported are headache, pump inhibitors (PPIs) have become one of the most com- diarrhea, abdominal pain, and nausea. The etiology of these monly prescribed classes of medications in the world. In side effects, particularly diarrhea, may be related to alter- 2007, PPI sales in the United States ~vere in excess of$1 ! bil- ations in gut flora caused by acid suppression50 The only lion5 Esomeprazole and lansoprazole both ranked among contraindication to the use of PPIs is a known history of the top five drugs sold in the United States in 20075 hypersensitivity to this class of medications. PPIs do not Overall, with their high safety profile and demonstrated require dosage adjustment in renal or hepatic dysfunction. efficacy, PPIs represent a major advance in the treatment of acid-related disorders ranging from peptic ulcer disease to Indications and Approved Uses erosive esophagitis. However, it has been shown that PPIs are PPls are accepted for the treatment and remission mainte- often misused and overused, which may have significant nance of acute gastric and duodenal ulcers, symptomatic gas- -7 implications? With the widespread and frequent long-term troesophageal reflux disease (GERD), erosive esopha~gitis, use of PPls, several adverse effects have come to light that pathological hypersecretory conditions such as Zollinger- may call for more selective prescribing practices, particularly Ellison syndrome, nonsteroidal anti-inflammatory drug- in older adults who may be more vulnerable and likely to induced gastric ulcers, and eradication of Helicoba/terpy/ori suffer the consequences of such adverse effects. With an esti- (Table I). mated 8% of males and 15% of females age 65 years and In 2008, the American College of Cardiology Foundation older experiencing reflux and potentially using acid-suppres- Task Force on Clinical Expert Consensus Documents pub- sive therapy,8 understanding the risks for potential adverse lished recommendations regarding the utilizaqon of PPIs to effects associated with PPls is critical in this population. decrease the risk of upper-gastrointestinal (GI)’ events associ- In this article, we review the current data on selected neg- ated *vith antiplatelet therapy for primary or secondary treat- ative outcomes that may result from PPI use. Specifically, ment of cardiovascular disease54 The recommendations sug- increasing evidence demonstrates that PPI therapy may be gest that PPIs should be used in the following clinical situa- associated with the development of Clostridium di~cile Conllkqo tions in order to reduce risks of GI bleeding: when patients infections, hip fractures, community-acquired pneumonia, ~vhich la are taking aspirin or dopidogrel and have a history of an ment of vitamin B12 deficiency, and possibly immunoglobulin E- ~ . ulcer (either bleeding or nonbleeding); or when p~tlents are "stress" mediated allergic reactions. The implications of such adverse taking dua! antiplatelet therapy or concomitant anficoagula- outcomes, along with the evidence of the inappropriate use teroids tion therapy24 of PPIs, underscore the need for more judicious use of this class of medications. inpatien Overuse/Misuse Drug Pathophysiology While it is clear that PPI therapy can be beneficial ~vhen used appropriately in the treatment of various GI disorders, and/or PPIs achieve acid suppression by binding to a specific evidence suggests that PPls are often overused and misused?r not clini { enzyme on the parietal cell, known as the proton pump, In many cases, PPIs are initiated or continued for prolonged resulting in inhibition of gastric acid secretion by the proton tematic 9 periods of time, without sufficient evaluation of the need for pump. PPIs are generally well tolerated. The overall inci- therapy. In fact, Manoharan et al,5 showed that in more than polyphal sequenc{ half of elderly inpatients who were prescribed acid-suppres- affect th. Dr. Kapadia is a Family Medicine Physician, Grand Junction sion therapy upon hospital discharge, there was no clearly COll~lnol VA Medical Center, Grand Junction, CO; Dr. Wynn is a Fami- documented indication for such therapy. Another study by ly Medicine Physician, Community Health Center of Meriden, 4 nifedipii Meriden, CT; and Dr. Salzman is Assistant Professor, Nardino and colleagues showed that 65% of medical inpa- affect th tients who xvere prescribed PPIs did not have an approved Department of Family and Community Medicine, Division of tion, PP Geriatric Medicine, Thomas Jefferson University Hospital, indication for use. Yet another study conducted at a major system a Philadelphia, PA. Australian teaching hospital showed that 63% of medical also usi~: inpatients were receiving PPIs for unapproved indications? greatest 24 Clinical Geriatrics July/August 2010 FDA-Approved Indications for PPI Use and Duration of Therapya Indications Duration of Therapy Acute gastric and duodenal ulcers 4-8 wk Maintenance of healed duodenal ulcer Unknown Symptomatic GERDb 4 wk (omeprazole) or 8 wk (lansoprazole) Erosive esophagitis 4-8 wk Maintenance of erosive esophagitis Unknown Zollinger-Ellison syndrome Several yrs NSAID-induced gastric ulcer prophylaxis Duration of NSAID NSAID-induced gastric ulcers 4-8 wk Eradication of Helicobacterpylori 7-14 days with tr pie antibiotics (meta-analyses and controlled studies have indicated littie clinical utility beyond 7 days) FDA = Food and Drug Administration," PPI = proton pump inhibitor; GERD = gastroesophageal reflux disease; NSAID = nonsteroidal and-inflam- matory drug, a Contains information from references 10 and 12. Atypical symptoms of GERD, such as early satiety, odynophagia, and weight loss, should be investigated with an upper endoscopy prior to eropiric initiation of an acid-suppressive agent, Effects of Concomitant Use of PPIs with Commonly Prescribed Medications in the Elderlya Drug Affect of PPI on Metabol sm Chmcal Relevance Digoxin ’ Increases absorption I Increase in digoxin levels and digoxin-associated toxicity , , Nifedipine Increases absorption Hypotension, shock, coma Warfarin Decreases metabolism Elevation in INR, b eeding PPI = proton pump inhibitor; INR = international normalized ratio. Contains information from references 10, 17-20. Common examples of unapproved utilizations of PPIs, studies have shown that the ~nmadon of omeprazole can which lack evidence to support their practice, involve treat- increase the absorption of digoxin, resulting in toxic digoxin ment of low-risk inpatients as a means of prophylaxis against levels,’8’~9 and can decrease the metabolism of warfarin,’7 "stress" ulcers and concurrent administration with corticos- resulting in an increased international normalized ratio reroids to prevent peptic ulcer disease in noncritically ill (INR) and bleeding,z° inpatiems)-7 In January 2009, the Food and Drug Administration released an early communication about the potential interac- Drug Interactions and Polypharmacy tions between omeprazole and clopidogrel.~’ The concern I)o/)~/)/Jarr,~ac;y, defined as the use of multiple medications that omeprazole may lower the efficacy of clopidogrel and/or the administration of multiple medications that are remains controversial and unsubstantiated given that avail- not clinically indicated,~6 is a common and potentially prob- able studies show conflicting results.22-25 However, a recent lematic occurrence in the elderly. One consequence of large, retrospective cohort study by Ho et a126 found that polypharmacy is drug interaction. This is an important con- patients taking a PPI and clopidogrel post-acute coronary sequence to consider when initiating PPIs since they can syndrome have a modest increased risk of death or rehospi- affect the absorption and metabolism of several medications talization as compared to those patients taking clopidogrel commonly prescribed in the elderly, such as digoxin, alone (odds ratio [OR], 1.25; 95% confidence interval [CI], nifedipine, and warfarin,l° By altering gastric pH, PPIs can 1.11-1.4). The results of this study suggest that the risks and affect the bioavailability of different medications. ~7 In addi- benefits of PPI therapy in patients taking clopidogrel should tion, PPls are metabolized by the hepatic cytochrome P450 be carefully considered. Further research studies released in system and thereby can affect the metabolism of medications 2010 continue to show conflicting results.27’’-8 Overall, there also using this system (Table II). Omeprazole possesses the are strong pharmacodynamic data suggesting that an inter- greatest potential for altering the P450 system. For instance, action exists between clopidogrel and PPIs; however, the Clinical Geriatrics July/August 2010 25 Although CDAD was more strongly associated with antibiot- c Overall i use (OR, 13.1; 95% CI, 6.6-26.1), the results suggest that ranging f There is enough evidence the risk of CDAD in hospitalized patients receiving antibi- ment of ( otics may be compounded by exposure to PPI therapy,e° to warrant concern about In 2004, Dial and colleagues~1 conducted a cohort study PPls a involving 1187 inpatients who received antibiotics. Within In addi the possible role of PPIs in this cohort, patients who had also received a PPI or H2 a role in blocker were compared to patients